Rheumatoid arthritis (RA) is a disease that sequentially progresses through several stages from its earliest asymptomatic origins characterized by autoantibodies alone through to a fully established and chronic destructive arthritis. Established RA is also characterized by several phenotypic subgroups that vary by genotype, autoantibodies, and environmental exposures. The central hypothesis of this Clinical and Technology Research Site (CTRS) proposal is that RA can be deconstructed such that novel disease stage- and cell lineage-specific therapeutic targets can be identified through the comprehensive evaluation of the linked adaptive and effector arms of the immune system. Reflecting this focus over the full spectrum of disease, the study is designated EMORA (Evolving Mechanisms of Rheumatoid Arthritis). In aggregate, the EMORA clinical and technology site investigators have several existing cohorts and decades of successful collaborations, and together constitute an integrated network of sites with clinical studies expertise, advanced technologies to identify and characterize antigen-specific lymphocytes, and capabilities to process and study synovium using many innovative technologies. EMORA will utilize a core strategy wherein paired peripheral blood and synovial samples are obtained and studied in a highly coordinated manner, and populations of T and B lymphocytes, fibroblast like synoviocytes and monocytic osteoclast precursors will be evaluated as single cells and small homogeneous populations. Using these approaches, EMORA investigators will test three primary hypotheses: 1) Novel mechanisms of disease and distinct therapeutic targets in RA can be discovered that will vary by the stage of development of disease, ranging from subjects at extraordinarily high risk for incipient clinical disease onset through to those with established RA under treatment, 2) Therapeutic targets will be identifiable in both antigen-specific circulating and tissue infiltrating B and T cells that react with RA- related autoantigens, necessitating paire studies of both peripheral blood and synovium, and 3) Exploration of networks of synovial effector cells including fibroblast-like synoviocytes and monocytic osteoclast precursors, identified in both peripheral blood and synovium, will identify novel pathways and related disease targets that drive inflammation, cartilage destruction and bone loss. Finally, to develop expertise going forward in ultrasound-guided synovial biopsy techniques, a `hands-on procedural education and evaluation program for USA investigators has been developed with Professor Paul Emery at the University of Leeds.